[Thread]
Two #ASGCT20 morning sessions focused on lung delivery. Cool work, but it seems to me that the big issues for clinical stage haven't really been addressed:
#AAV can target specific cell types in the lung, and multiple groups have rescued mouse models of genetic diseases. But both new and old lung-trophic capsids seem to hit T2 epithelial cells, which turn over and lose non-integrating transgenes.
Why does the virus end up in these cells? Are the T1 cells designed to reject microbes? What about fibroblasts and other cells, that do get transduced in some tissues?
Other teams are testing #LNPs. I think getting the particles where they need to be is challenging: IV delivery ends up in the liver, aerosol is hard in practice, and tracheal injection isn't a great solution for humans. Plus the lung is full of slime etc, especially in disease.
Further, I imagine the need for highly consistent production batches for #GMP combined with need for frequent redosing of #mRNA-based therapies might make clinical-scale production very challenging. But maybe companies like @moderna_tx are on top of this?
People are trying #Exosomes, naked oligos, and biopolymers for slow release. I didn't catch those talks, but I imagine exosomes have all the production issues of LNPs, at least for now.
I'm not an expert on #lung gene delivery, these are just my impressions, combined with the observation that we've been trying for a long time with limited success. Would love to hear from people who understand this better.
Looking forward to @DahlmanLab's talk at 14:25 EST for more #LNP tricks!
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